Gene mutations cause abnormal vessels in cell model
Using cells from patients, researchers at IGP have created a model for studying the disease cerebral cavernous malformation. In the model they found that mutations in a specific gene are sufficient to induce the abnormal vessels that characterise the disease. This knowledge may contribute to the development of new treatment strategies for cerebral cavernous malformation.
Blood vessel organoid where different cells are visualised by staining the proteins VE-cadherin (green) and alpha smooth muscle actin (magenta) Image: Maximiliano Arce
Cerebral Cavernous Malformation (CCM) is a neurovascular disease where blood vessel lesions are formed which can cause hemorrhages, and in some cases, acute bleedings (stroke). With surgery being the only treatment strategy, a better understanding of the genetic alterations in CCM is crucial for finding alternative therapeutic options for the disease.
To study the human brain and its diseases experimentally, there is a need for models that mimic brain tissues as much as possible. In the current study, the researchers generated induced pluripotent stem cells (iPSCs) from blood cells from CCM patients. The aim was to test their potential as a human preclinical model and to explore how certain mutations affect CCM pathology.
“We created iPSC lines from three patients with inherited mutations in the gene KRIT1. From these we generated microscopic organs called organoids, which recreate key aspects during early blood vessel formation. In the organoids we could subsequently study the role of KRIT1 mutations. We saw that organoids from CCM patients exhibited enlarged and abnormal vascular structures where the cells in the vessel walls were not properly connected. They therefore had a similar morphology to vessels found in CCM patients,” says Maximiliano Arce, researcher at IGP and first author of the study.
In another experiment, the researchers tested to inject blood vessel cells derived from iPSCs into brain explants from mice. They found that cells from CCM patients integrated into the normal vasculature and created vascular anomalies.
“Our results show that blood vessels cells with a mutated KRIT1 gene can disrupt blood brain vascular quiescence and promote the formation of vascular abnormalities. In addition, we have shown that iPSC lines from CCM patients can serve as the basis for developing experimental human models to investigate underlying disease mechanisms in CCM,” says Peetra Magnusson who led the study.
The study was performed in collaboration with researchers in Italy, Finland and UK. It has been published in the scientific journal Cell Reports.